HIV-1 specific CTL appear to be crucial in the control of HIV-1 viral replication in vivo; in untreated individuals, a strong inverse correlation between circulating CTL frequency and plasma viral load has been observed. New combination antiretroviral therapies have dramatically decreased AIDS related mortality in the United States, and many acute and chronically infected individuals are being treated with these powerful antiretroviral agents. However, the impact of these therapies on the HIV-1 specific CTL response is unknown; The goal of this initial independent research project is to investigate the dynamics of HIV-1 specific CTL in HIV-1 infection. In specific aim 1, the PI will examine the effect of drug treatment on the HIV-1 specific CTL response, whether effector and memory CTL decline in frequency following drug therapy, and whether this is related to time of initiation of treatment. The quality of the immune response will be assessed by analysis of the breadth of antigens recognized. Some patients entered on drug trials will not adhere to drug regimens due to adverse events or difficulties in compliance; in specific aim 2, the quantity and kinetics of CTL change will be measured in relation to virus breakthrough. In addition, the PI will determine if breakthrough virus has escaped from CTL control. In a small number of patients who have controlled their plasma viremia after drug discontinuation the immune correlates of viral containment will be examined and the dynamics of CTL change in relation to viral load will be modeled. Finally, the PI and co-workers have observed a very high frequency of circulating CTL effectors in some long term non- progressors. In specific aim 3 the number of CTL will be correlated with viral load using sensitive PCR techniques. These studies of CTL dynamics will likely contribute considerably to understanding the role of HIV-1 specific CTL and vaccine strategies designed to induce CTL in the context of a prophylactic anti-HIV-1 vaccine.